The pathogenicity and virulence of Leishmania - interplay of virulence factors with host defenses

References

• Mann S, Frasca K, Scherrer S, et al. A review of Leishmaniasis: current knowledge and future directions. Curr Trop Med Rep. 2021;8:121–132.
   PubMedGoogle Scholar
• Farrar J, Hotez PJ, Junghanss T, et al. Manson’s tropical diseases E-book. Elsevier Health Sci. 2013. ISBN:978-0-7020-5101-2.
   Google Scholar
• Singh OP, Tiwary P, Kushwaha AK, et al. Xenodiagnosis to evaluate the infectiousness of humans to sandflies in an area endemic for visceral leishmaniasis in Bihar, India: a transmission-dynamics study. Lancet Microbe. 2021;2:e23–e31.
   PubMedGoogle Scholar
• Nazzaro G, Rovaris M, Veraldi S. Leishmaniasis: a disease with many names. JAMA Dermatol. 2014;150:1204.
   PubMed Web of Science ®Google Scholar
• Lainson R, Ryan L, Shaw JJ. Infective stages of Leishmania in the sandfly vector and some observations on the mechanism of transmission. Memórias Inst Oswaldo Cruz. 1987;82:421–424.
   PubMedGoogle Scholar
• Real F, Florentino PT, Reis LC, et al. Cell-to-cell transfer of Leishmania amazonensis amastigotes is mediated by immunomodulatory LAMP-rich parasitophorous extrusions. Cell Microbiol. 2014;16:1549–1564.
   PubMed Web of Science ®Google Scholar
• Esch KJ, Petersen CA. Transmission and epidemiology of zoonotic protozoal diseases of companion animals. Clin Microbiol Rev. 2013;26:58–85.
   PubMed Web of Science ®Google Scholar
• ELkhair EB. Elevated cortisol level due to visceral leishmaniasis and skin hyper-pigmentation are causally related. Int J Sci Commer Humanit. 2014;2:7.
   Google Scholar
• Ready PD. Epidemiology of visceral leishmaniasis. Clin Epidemiol. 2014;6:147.
   PubMed Web of Science ®Google Scholar
• Malla N, Mahajan R. Pathophysiology of visceral leishmaniasis-some recent concepts. Indian J Med Res. 2006;123:267.
   PubMed Web of Science ®Google Scholar
• Stark D, Pett S, Marriott D, et al. Post-kala-azar dermal leishmaniasis due to Leishmania infantum in a human immunodeficiency virus type 1-infected patient. J Clin Microbiol. 2006;44:1178–1180.
   PubMed Web of Science ®Google Scholar
• Organization WH, Zijlstra E, Alvar J. The Post Kala-azar Dermal Leishmaniasis (PKDL) atlas. A manual for health workers. 2012. ISBN:9789241504102.
   Google Scholar
• Zijlstra E, Musa A, Khalil E, et al. Post-kala-azar dermal leishmaniasis. Lancet Infect Dis. 2003;3:87–98.
   PubMed Web of Science ®Google Scholar
• Zijlstra EE. PKDL and other dermal lesions in HIV co-infected patients with leishmaniasis: review of clinical presentation in relation to immune responses. PLoS Negl Trop Dis. 2014;8:e3258.
   PubMed Web of Science ®Google Scholar
• Pavli A, Maltezou HC. Leishmaniasis, an emerging infection in travelers. Int J Infect Dis. 2010;14:e1032–9.
   PubMed Web of Science ®Google Scholar
• Reithinger R, Davies CR. Is the domestic dog (Canis familiaris) a reservoir host of American cutaneous leishmaniasis? A critical review of the current evidence. Am J Trop Med Hyg. 1999;61:530–541.
   PubMed Web of Science ®Google Scholar
• Dantas-Torres F. Canine leishmaniasis in South America. Parasit Vectors. 2009;2(Suppl 1):S1.
   PubMedGoogle Scholar
• Chan A, Ayala JM, Alvarez F, et al. The role of Leishmania GP63 in the modulation of innate inflammatory response to Leishmania major infection. PLoS One. 2021;16:e0262158.
   PubMed Web of Science ®Google Scholar
• Saraiva EM, Pinto-da-silva LH, Wanderley JL, et al. Flow cytometric assessment of Leishmania spp metacyclic differentiation: validation by morphological features and specific markers. Exp Parasitol. 2005;110:39–47.
   PubMed Web of Science ®Google Scholar
• Pimenta PF, Saraiva EM, Sacks DL. The comparative fine structure and surface glycoconjugate expression of three life stages of Leishmania major. Exp Parasitol. 1991;72:191–204.
   PubMed Web of Science ®Google Scholar
• Wilson ME, Hardin KK, Donelson JE. Expression of the major surface glycoprotein of Leishmania donovani chagasi in virulent and attenuated promastigotes. J Immunol. 1989;143:678–684.
   PubMed Web of Science ®Google Scholar
• van Zandbergen G, Bollinger A, Wenzel A, et al. Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum. Proc Natl Acad Sci U S A. 2006;103:13837–13842.
   PubMed Web of Science ®Google Scholar
• Mosser DM, Brittingham A. Leishmania, macrophages and complement: a tale of subversion and exploitation. Parasitology. 1997;115(Suppl):S9–23.
   PubMedGoogle Scholar
• Descoteaux A, Luo Y, Turco SJ, et al. A specialized pathway affecting virulence glycoconjugates of Leishmania. Science. 1995;269:1869–1872.
   PubMed Web of Science ®Google Scholar
• Favila MA, Geraci NS, Jayakumar A, et al. Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells. PLoS Negl Trop Dis. 2015;9:e0004238.
   PubMed Web of Science ®Google Scholar
• McConville MJ, Schnur LF, Jaffe C, et al. Structure of Leishmania lipophosphoglycan: inter- and intra-specific polymorphism in old world species. Biochem J. 1995;310(Pt 3):807–818.
   PubMedGoogle Scholar
• Camara M, Ortiz G, Valero PL, et al. Complement-mediated lysis and infectivity for mouse macrophages and sandflies of virulent and attenuated Leishmania major promastigotes varying in expression of the major surface protease and lipophosphoglycan. Ann Trop Med Parasitol. 1995;89:243–251.
   PubMed Web of Science ®Google Scholar
• Chakraborty R, Chakraborty P, Basu MK. Macrophage mannosyl fucosyl receptor: its role in invasion of virulent and avirulent L. donovani promastigotes. Biosci Rep. 1998;18:129–142.
   PubMed Web of Science ®Google Scholar
• Culley FJ, Harris RA, Kaye PM, et al. C-reactive protein binds to a novel ligand on Leishmania donovani and increases uptake into human macrophages. J Immunol. 1996;156:4691–4696.
   PubMed Web of Science ®Google Scholar
• Miao L, Stafford A, Nir S, et al. Potent inhibition of viral fusion by the lipophosphoglycan of Leishmania donovani. Biochemistry. 1995;34:4676–4683.
   PubMed Web of Science ®Google Scholar
• Spath GF, Epstein L, Leader B, et al. Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Proc Natl Acad Sci U S A. 2000;97:9258–9263.
   PubMed Web of Science ®Google Scholar
• Holm A, Tejle K, Magnusson KE, et al. Leishmania donovani lipophosphoglycan causes periphagosomal actin accumulation: correlation with impaired translocation of PKCalpha and defective phagosome maturation. Cell Microbiol. 2001;3:439–447.
   PubMed Web of Science ®Google Scholar
• Delgado-Dominguez J, Gonzalez-Aguilar H, Aguirre-Garcia M, et al. Leishmania mexicana lipophosphoglycan differentially regulates PKCalpha-induced oxidative burst in macrophages of BALB/c and C57BL/6 mice. Parasite Immunol. 2010;32:440–449.
   PubMed Web of Science ®Google Scholar
• Scianimanico S, Desrosiers M, Dermine JF, et al. Impaired recruitment of the small GTPase rab7 correlates with the inhibition of phagosome maturation by Leishmania donovani promastigotes. Cell Microbiol. 1999;1:19–32.
   PubMed Web of Science ®Google Scholar
• Chan J, Fujiwara T, Brennan P, et al. Microbial glycolipids: possible virulence factors that scavenge oxygen radicals. Proc Natl Acad Sci U S A. 1989;86:2453–2457.
   PubMed Web of Science ®Google Scholar
• Eilam Y, El-On J, Spira DT. Leishmania major: excreted factor, calcium ions, and the survival of amastigotes. Exp Parasitol. 1985;59:161–168.
   PubMed Web of Science ®Google Scholar
• Lodge R, Diallo TO, Descoteaux A. Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane. Cell Microbiol. 2006;8:1922–1931.
   PubMed Web of Science ®Google Scholar
• Hatzigeorgiou DE, Geng J, Zhu B, et al. Lipophosphoglycan from Leishmania suppresses agonist-induced interleukin 1 beta gene expression in human monocytes via a unique promoter sequence. Proc Natl Acad Sci U S A. 1996;93:14708–14713.
   PubMed Web of Science ®Google Scholar
• Gupta G, Oghumu S, Satoskar AR. Mechanisms of immune evasion in leishmaniasis. Adv Appl Microbiol. 2013;82:155–184.
   PubMed Web of Science ®Google Scholar
• Contreras I, Gomez MA, Nguyen O, et al. Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63. PLoS Pathog. 2010;6:e1001148.
   PubMed Web of Science ®Google Scholar
• Ilg T. Lipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana. EMBO J. 2000;19:1953–1962.
   PubMed Web of Science ®Google Scholar
• Allahverdiyev AM, Cakir Koc R, Bagirova M, et al. A new approach for development of vaccine against visceral leishmaniasis: lipophosphoglycan and polyacrylic acid conjugates. Asian Pac J Trop Med. 2017;10:877–886.
   PubMed Web of Science ®Google Scholar
• Topuzogullari M, Cakir Koc R, Dincer Isoglu S, et al. Conjugation, characterization and toxicity of lipophosphoglycan-polyacrylic acid conjugate for vaccination against leishmaniasis. J Biomed Sci. 2013;20:35.
   PubMed Web of Science ®Google Scholar
• Martinez Salazar MB, Delgado Dominguez J, Silva Estrada J, et al. Vaccination with Leishmania mexicana LPG induces PD-1 in CD8(+) and PD-L2 in macrophages thereby suppressing the immune response: a model to assess vaccine efficacy. Vaccine. 2014;32:1259–1265.
   PubMed Web of Science ®Google Scholar
• Descoteaux A, Avila HA, Zhang K, et al. Leishmania LPG3 encodes a GRP94 homolog required for phosphoglycan synthesis implicated in parasite virulence but not viability. EMBO J. 2002;21:4458–4469.
   PubMed Web of Science ®Google Scholar
• Larreta R, Guzman F, Patarroyo ME, et al. Antigenic properties of the Leishmania infantum GRP94 and mapping of linear B-cell epitopes. Immunol Lett. 2002;80:199–205.
   PubMed Web of Science ®Google Scholar
• Pessenda G, da Silva JS. Arginase and its mechanisms in Leishmania persistence. Parasite Immunol. 2020;42:e12722.
   PubMed Web of Science ®Google Scholar
• Muleme HM, Reguera RM, Berard A, et al. Infection with arginase-deficient Leishmania major reveals a parasite number-dependent and cytokine-independent regulation of host cellular arginase activity and disease pathogenesis. J Immunol. 2009;183:8068–8076.
   PubMed Web of Science ®Google Scholar
• Lopez M, Cherkasov A, Nandan D. Molecular architecture of leishmania EF-1 alpha reveals a novel site that may modulate protein translation: a possible target for drug development. Biochem Biophys Res Commun. 2007;356:886–892.
   PubMed Web of Science ®Google Scholar
• Nandan D, Reiner NE. Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1. Clin Immunol. 2005;114:266–277.
   PubMed Web of Science ®Google Scholar
• Nandan D, Yi T, Lopez M, et al. Leishmania EF-1 alpha activates the Src homology 2 domain containing tyrosine phosphatase SHP-1 leading to macrophage deactivation. J Biol Chem. 2002;277:50190–50197.
   PubMed Web of Science ®Google Scholar
• Silverman JM, Chan SK, Robinson DP, et al. Proteomic analysis of the secretome of Leishmania donovani. Genome Biol. 2008;9:R35.
   PubMed Web of Science ®Google Scholar
• Silverman JM, Clos J, De’oliveira CC, et al. An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages. J Cell Sci. 2010;123:842–852.
   PubMed Web of Science ®Google Scholar
• Sabur A, Bhowmick S, Chhajer R, et al. Liposomal elongation factor-1 alpha triggers effector CD4 and CD8 T cells for induction of long-lasting protective immunity against visceral leishmaniasis. Front Immunol. 2018;9:18.
   PubMed Web of Science ®Google Scholar
• Perteguer MJ, Gomez-Puertas P, Canavate C, et al. Ddi1-like protein from Leishmania major is an active aspartyl proteinase. Cell Stress Chaperones. 2013;18:171–181.
   PubMed Web of Science ®Google Scholar
• Fong D, Chang KP. Surface antigenic change during differentiation of a parasitic protozoan, Leishmania mexicana: identification by monoclonal antibodies. Proc Natl Acad Sci U S A. 1982;79:7366–7370.
   PubMed Web of Science ®Google Scholar
• Mundodi V, Kucknoor AS, Gedamu L. Role of Leishmania (Leishmania) chagasi amastigote cysteine protease in intracellular parasite survival: studies by gene disruption and antisense mRNA inhibition. BMC Mol Biol. 2005;6:3.
   PubMed Web of Science ®Google Scholar
• Valdivieso E, Dagger F, Rascon A. Leishmania mexicana: identification and characterization of an aspartyl proteinase activity. Exp Parasitol. 2007;116:77–82.
   PubMed Web of Science ®Google Scholar
• Yao C, Donelson JE, Wilson ME. The major surface protease (MSP or GP63) of Leishmania sp. Biosynthesis, regulation of expression, and function. Mol Biochem Parasitol. 2003;132:1–16.
   PubMed Web of Science ®Google Scholar
• Bouvier J, Schneider P, Etges R, et al. Peptide substrate specificity of the membrane-bound metalloprotease of Leishmania. Biochemistry. 1990;29:10113–10119.
   PubMed Web of Science ®Google Scholar
• Schneider P, Rosat JP, Bouvier J, et al. Leishmania major: differential regulation of the surface metalloprotease in amastigote and promastigote stages. Exp Parasitol. 1992;75:196–206.
   PubMed Web of Science ®Google Scholar
• Ellis M, Sharma DK, Hilley JD, et al. Processing and trafficking of Leishmania mexicana GP63. Analysis using GP18 mutants deficient in glycosylphosphatidylinositol protein anchoring. J Biol Chem. 2002;277:27968–27974.
   PubMed Web of Science ®Google Scholar
• Matte C, Casgrain PA, Seguin O, et al. Leishmania major promastigotes evade LC3-associated phagocytosis through the action of GP63. PLoS Pathog. 2016;12:e1005690.
   PubMed Web of Science ®Google Scholar
• Chang KP, McGwire BS. Molecular determinants and regulation of Leishmania virulence. Kinetoplastid Biol Dis. 2002;1:1.
   PubMedGoogle Scholar
• Atayde VD, Aslan H, Townsend S, et al. Exosome secretion by the parasitic protozoan leishmania within the sand fly midgut. Cell Rep. 2015;13:957–967.
   PubMed Web of Science ®Google Scholar
• Yao C, Leidal KG, Brittingham A, et al. Biosynthesis of the major surface protease GP63 of Leishmania chagasi. Mol Biochem Parasitol. 2002;121:119–128.
   PubMed Web of Science ®Google Scholar
• Arango Duque G, Jardim A, Gagnon E, et al. The host cell secretory pathway mediates the export of Leishmania virulence factors out of the parasitophorous vacuole. PLoS Pathog. 2019;15:e1007982.
   PubMed Web of Science ®Google Scholar
• Brittingham A, Morrison CJ, McMaster WR, et al. Role of the Leishmania surface protease gp63 in complement fixation, cell adhesion, and resistance to complement-mediated lysis. J Immunol. 1995;155:3102–3111.
   PubMed Web of Science ®Google Scholar
• Mosser DM, Edelson PJ. The mouse macrophage receptor for C3bi (CR3) is a major mechanism in the phagocytosis of Leishmania promastigotes. J Immunol. 1985;135:2785–2789.
   PubMed Web of Science ®Google Scholar
• Brittingham A, Chen G, McGwire BS, et al. Interaction of Leishmania gp63 with cellular receptors for fibronectin. Infect Immun. 1999;67:4477–4484.
   PubMed Web of Science ®Google Scholar
• Kulkarni MM, Jones EA, McMaster WR, et al. Fibronectin binding and proteolytic degradation by Leishmania and effects on macrophage activation. Infect Immun. 2008;76:1738–1747.
   PubMed Web of Science ®Google Scholar
• McGwire BS, Chang KP, Engman DM. Migration through the extracellular matrix by the parasitic protozoan Leishmania is enhanced by surface metalloprotease gp63. Infect Immun. 2003;71:1008–1010.
   PubMed Web of Science ®Google Scholar
• Chaudhuri G, Chaudhuri M, Pan A, et al. Surface acid proteinase (gp63) of Leishmania mexicana. A metalloenzyme capable of protecting liposome-encapsulated proteins from phagolysosomal degradation by macrophages. J Biol Chem. 1989;264:7483–7489.
   PubMed Web of Science ®Google Scholar
• Chen DQ, Kolli BK, Yadava N, et al. Episomal expression of specific sense and antisense mRNAs in Leishmania amazonensis: modulation of gp63 level in promastigotes and their infection of macrophages in vitro. Infect Immun. 2000;68:80–86.
   PubMed Web of Science ®Google Scholar
• Matheoud D, Moradin N, Bellemare-Pelletier A, et al. Leishmania evades host immunity by inhibiting antigen cross-presentation through direct cleavage of the SNARE VAMP8. Cell Host Microbe. 2013;14:15–25.
   PubMed Web of Science ®Google Scholar
• Corradin S, Ransijn A, Corradin G, et al. MARCKS-related protein (MRP) is a substrate for the Leishmania major surface protease leishmanolysin (gp63). J Biol Chem. 1999;274:25411–25418.
   PubMed Web of Science ®Google Scholar
• Corradin S, Mauel J, Ransijn A, et al. Down-regulation of MARCKS-related protein (MRP) in macrophages infected with Leishmania. J Biol Chem. 1999;274:16782–16787.
   PubMed Web of Science ®Google Scholar
• Blanchette J, Racette N, Faure R, et al. Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation. Eur J Immunol. 1999;29:3737–3744.
   PubMed Web of Science ®Google Scholar
• Gomez MA, Contreras I, Halle M, et al. Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Sci Signal. 2009;2:ra58.
   PubMed Web of Science ®Google Scholar
• Abu-Dayyeh I, Shio MT, Sato S, et al. Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. PLoS Negl Trop Dis. 2008;2:e305.
   PubMed Web of Science ®Google Scholar
• Gregory DJ, Godbout M, Contreras I, et al. A novel form of NF-kappaB is induced by Leishmania infection: involvement in macrophage gene expression. Eur J Immunol. 2008;38:1071–1081.
   PubMed Web of Science ®Google Scholar
• Guizani-Tabbane L, Ben-Aissa K, Belghith M, et al. Leishmania major amastigotes induce p50/c-Rel NF-kappa B transcription factor in human macrophages: involvement in cytokine synthesis. Infect Immun. 2004;72:2582–2589.
   PubMed Web of Science ®Google Scholar
• Jaramillo M, Gomez MA, Larsson O, et al. Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection. Cell Host Microbe. 2011;9:331–341.
   PubMed Web of Science ®Google Scholar
• Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–687.
   PubMed Web of Science ®Google Scholar
• Shio MT, Christian JG, Jung JY, et al. PKC/ROS-mediated NLRP3 inflammasome activation is attenuated by leishmania zinc-metalloprotease during infection. PLoS Negl Trop Dis. 2015;9:e0003868.
   PubMed Web of Science ®Google Scholar
• Xu D, Liew FY. Protection against leishmaniasis by injection of DNA encoding a major surface glycoprotein, gp63, of L. major. Immunology. 1995;84:173–176.
   PubMed Web of Science ®Google Scholar
• Webb JR, Button LL, McMaster WR. Heterogeneity of the genes encoding the major surface glycoprotein of Leishmania donovani. Mol Biochem Parasitol. 1991;48:173–184.
   PubMed Web of Science ®Google Scholar
• Mazumder S, Maji M, Das A, et al. Potency, efficacy and durability of DNA/DNA, DNA/protein and protein/protein based vaccination using gp63 against Leishmania donovani in BALB/c mice. PLoS One. 2011;6:e14644.
   PubMed Web of Science ®Google Scholar
• Russo DM, Jardim A, Carvalho EM, et al. Mapping human T cell epitopes in leishmania gp63. Identification of cross-reactive and species-specific epitopes. J Immunol. 1993;150:932–939.
   PubMed Web of Science ®Google Scholar
• Sachdeva R, Banerjea AC, Malla N, et al. Immunogenicity and efficacy of single antigen Gp63, polytope and polytopeHSP70 DNA vaccines against visceral Leishmaniasis in experimental mouse model. PLoS One. 2009;4:e7880.
   PubMed Web of Science ®Google Scholar
• Rezvan H, Rees R, Ali S. Leishmania mexicana Gp63 cDNA using gene gun induced higher immunity to L. mexicana infection compared to soluble leishmania antigen in BALB/C. Iran J Parasitol. 2011;6:60–75.
   PubMed Web of Science ®Google Scholar
• Bhowmick S, Ravindran R, Ali N. gp63 in stable cationic liposomes confers sustained vaccine immunity to susceptible BALB/c mice infected with Leishmania donovani. Infect Immun. 2008;76:1003–1015.
   PubMed Web of Science ®Google Scholar
• Sajid M, McKerrow JH. Cysteine proteases of parasitic organisms. Mol Biochem Parasitol. 2002;120:1–21.
   PubMed Web of Science ®Google Scholar
• Selzer PM, Pingel S, Hsieh I, et al. Cysteine protease inhibitors as chemotherapy: lessons from a parasite target. Proc Natl Acad Sci U S A. 1999;96:11015–11022.
   PubMed Web of Science ®Google Scholar
• Sakanari JA, Nadler SA, Chan VJ, et al. Leishmania major: comparison of the cathepsin L- and B-like cysteine protease genes with those of other trypanosomatids. Exp Parasitol. 1997;85:63–76.
   PubMed Web of Science ®Google Scholar
• Hide M, Banuls AL. Polymorphisms of cpb multicopy genes in the Leishmania (Leishmania) donovani complex. Trans R Soc Trop Med Hyg. 2008;102:105–106.
   PubMed Web of Science ®Google Scholar
• Marin-Villa M, Vargas-Inchaustegui DA, Chaves SP, et al. The C-terminal extension of Leishmania pifanoi amastigote-specific cysteine proteinase Lpcys2: a putative function in macrophage infection. Mol Biochem Parasitol. 2008;162:52–59.
   PubMed Web of Science ®Google Scholar
• Pereira BA, Silva FS, Rebello KM, et al. In silico predicted epitopes from the COOH-terminal extension of cysteine proteinase B inducing distinct immune responses during Leishmania (Leishmania) amazonensis experimental murine infection. BMC Immunol. 2011;12:44.
   PubMed Web of Science ®Google Scholar
• Lasakosvitsch F, Gentil LG, Dos Santos MR, et al. Cloning and characterisation of a cysteine proteinase gene expressed in amastigotes of Leishmania (L.) amazonensis. Int J Parasitol. 2003;33:445–454.
   PubMed Web of Science ®Google Scholar
• Denise H, Poot J, Jimenez M, et al. Studies on the CPA cysteine peptidase in the Leishmania infantum genome strain JPCM5. BMC Mol Biol. 2006;7:42.
   PubMed Web of Science ®Google Scholar
• Mahmoudzadeh-Niknam H, McKerrow JH. Leishmania tropica: cysteine proteases are essential for growth and pathogenicity. Exp Parasitol. 2004;106:158–163.
   PubMed Web of Science ®Google Scholar
• Alexander J, Coombs GH, Mottram JC. Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. J Immunol. 1998;161:6794–6801.
   PubMed Web of Science ®Google Scholar
• Buxbaum LU, Denise H, Coombs GH, et al. Cysteine protease B of Leishmania mexicana inhibits host Th1 responses and protective immunity. J Immunol. 2003;171:3711–3717.
   PubMed Web of Science ®Google Scholar
• Bhardwaj N, Rosas LE, Lafuse WP, et al. Leishmania inhibits STAT1-mediated IFN-gamma signaling in macrophages: increased tyrosine phosphorylation of dominant negative STAT1beta by Leishmania mexicana. Int J Parasitol. 2005;35:75–82.
   PubMed Web of Science ®Google Scholar
• Boom WH, Liebster L, Abbas AK, et al. Patterns of cytokine secretion in murine leishmaniasis: correlation with disease progression or resolution. Infect Immun. 1990;58:3863–3870.
   PubMed Web of Science ®Google Scholar
• Doroud D, Zahedifard F, Vatanara A, et al. C-terminal domain deletion enhances the protective activity of cpa/cpb loaded solid lipid nanoparticles against Leishmania major in BALB/c mice. PLoS Negl Trop Dis. 2011;5:e1236.
   PubMed Web of Science ®Google Scholar
• Zadeh-Vakili A, Taheri T, Taslimi Y, et al. Immunization with the hybrid protein vaccine, consisting of Leishmania major cysteine proteinases Type I (CPB) and Type II (CPA), partially protects against leishmaniasis. Vaccine. 2004;22:1930–1940.
   PubMed Web of Science ®Google Scholar
• Das A, Asad M, Sabur A, et al. Monophosphoryl lipid A based cationic liposome facilitates vaccine induced expansion of polyfunctional T cell immune responses against visceral leishmaniasis. ACS Appl Bio Mater. 2018;1:999–1018.
   PubMedGoogle Scholar
• Swenerton RK, Zhang S, Sajid M, et al. The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion. J Biol Chem. 2011;286:429–440.
   PubMed Web of Science ®Google Scholar
• Munday JC, McLuskey K, Brown E, et al. Oligopeptidase B deficient mutants of Leishmania major. Mol Biochem Parasitol. 2011;175:49–57.
   PubMed Web of Science ®Google Scholar
• Swenerton RK, Knudsen GM, Sajid M, et al. Leishmania subtilisin is a maturase for the trypanothione reductase system and contributes to disease pathology. J Biol Chem. 2010;285:31120–31129.
   PubMed Web of Science ®Google Scholar
• Pinheiro RO, Pinto EF, Lopes JR, et al. TGF-beta-associated enhanced susceptibility to leishmaniasis following intramuscular vaccination of mice with Leishmania amazonensis antigens. Microbes Infect. 2005;7:1317–1323.
   PubMed Web of Science ®Google Scholar
• Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol. 2008;9:679–690.
   PubMed Web of Science ®Google Scholar
• Damianou A, Burge RJ, Catta-Preta CMC, et al. Essential roles for deubiquitination in Leishmania life cycle progression. PLoS Pathog. 2020;16:e1008455.
   PubMed Web of Science ®Google Scholar
• Azevedo CS, Guido BC, Pereira JL, et al. Revealing a novel Otubain-like enzyme from leishmania infantum with deubiquitinating activity toward K48-linked substrate. Front Chem. 2017;5:13.
   PubMed Web of Science ®Google Scholar
• Kamran M, Ejazi SA, Choudhury ST, et al. a novel antigen, Otubain Cysteine Peptidase of Leishmania donovani, for the Serodiagnosis of Visceral Leishmaniasis and for monitoring treatment response. Clin Infect Dis. 2021;73:1281–1283.
   PubMed Web of Science ®Google Scholar
• Krobitsch S, Clos J. A novel role for 100 kD heat shock proteins in the parasite Leishmania donovani. Cell Stress Chaperones. 1999;4:191–198.
   PubMed Web of Science ®Google Scholar
• Hubel A, Krobitsch S, Horauf A, et al. Leishmania major Hsp100 is required chiefly in the mammalian stage of the parasite. Mol Cell Biol. 1997;17:5987–5995.
   PubMed Web of Science ®Google Scholar
• Abrahao J, Mokry DZ, Ramos CHI. Hsp78 (78 kDa heat shock protein), a representative AAA family member found in the mitochondrial matrix of saccharomyces cerevisiae. Front Mol Biosci. 2017;4:60.
   PubMed Web of Science ®Google Scholar
• Das S, Banerjee A, Kamran M, et al. A chemical inhibitor of heat shock protein 78 (HSP78) from Leishmania donovani represents a potential antileishmanial drug candidate. J Biol Chem. 2020;295:9934–9947.
   PubMedGoogle Scholar
• Haslbeck M, Franzmann T, Weinfurtner D, et al. Some like it hot: the structure and function of small heat-shock proteins. Nat Struct Mol Biol. 2005;12:842–846.
   PubMed Web of Science ®Google Scholar
• Hombach A, Ommen G, MacDonald A, et al. A small heat shock protein is essential for thermotolerance and intracellular survival of Leishmania donovani. J Cell Sci. 2014;127:4762–4773.
   PubMed Web of Science ®Google Scholar
• Folgueira C, Requena JM. A postgenomic view of the heat shock proteins in kinetoplastids. FEMS Microbiol Rev. 2007;31:359–377.
   PubMed Web of Science ®Google Scholar
• Hombach A, Ommen G, Sattler V, et al. Leishmania donovani P23 protects parasites against HSP90 inhibitor-mediated growth arrest. Cell Stress Chaperones. 2015;20:673–685.
   PubMed Web of Science ®Google Scholar
• Batista FA, Almeida GS, Seraphim TV, et al. Identification of two p23 co-chaperone isoforms in Leishmania braziliensis exhibiting similar structures and Hsp90 interaction properties despite divergent stabilities. FEBS J. 2015;282:388–406.
   PubMed Web of Science ®Google Scholar
• Garin YJ, Meneceur P, Pratlong F, et al. A2 gene of old world cutaneous Leishmania is a single highly conserved functional gene. BMC Infect Dis. 2005;5:18.
   PubMed Web of Science ®Google Scholar
• Fernandes AP, Canavaci AMC, McCall L-I, et al. A2 and other visceralizing proteins of Leishmania: role in pathogenesis and application for vaccine development. Prot Proteomics Leishmania Trypanosoma. 2014;74:77–101.
   Google Scholar
• Zhang WW, Charest H, Ghedin E, et al. Identification and overexpression of the A2 amastigote-specific protein in Leishmania donovani. Mol Biochem Parasitol. 1996;78:79–90.
   PubMed Web of Science ®Google Scholar
• Zhang WW, Matlashewski G. Loss of virulence in Leishmania donovani deficient in an amastigote-specific protein, A2. Proc Natl Acad Sci U S A. 1997;94:8807–8811.
   PubMed Web of Science ®Google Scholar
• Zhang WW, Mendez S, Ghosh A, et al. Comparison of the A2 gene locus in Leishmania donovani and Leishmania major and its control over cutaneous infection. J Biol Chem. 2003;278:35508–35515.
   PubMed Web of Science ®Google Scholar
• Ghosh A, Zhang WW, Matlashewski G. Immunization with A2 protein results in a mixed Th1/Th2 and a humoral response which protects mice against Leishmania donovani infections. Vaccine. 2001;20:59–66.
   PubMed Web of Science ®Google Scholar
• Freitas-Mesquita AL, Dos-Santos ALA, Meyer-Fernandes JR. Involvement of Leishmania phosphatases in parasite biology and pathogeny. Front Cell Infect Microbiol. 2021;11:633146.
   PubMed Web of Science ®Google Scholar
• Nascimento M, Zhang WW, Ghosh A, et al. Identification and characterization of a protein-tyrosine phosphatase in Leishmania: involvement in virulence. J Biol Chem. 2006;281:36257–36268.
   PubMed Web of Science ®Google Scholar
• Green SJ, Meltzer MS, Hibbs J, et al. Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol. 1990;144:278–283.
   PubMed Web of Science ®Google Scholar
• Liew F, Millott S, Parkinson C, et al. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol. 1990;144:4794–4797.
   PubMed Web of Science ®Google Scholar
• Forget G, Gregory DJ, Whitcombe LA, et al. Role of host protein tyrosine phosphatase SHP-1 in Leishmania donovani-induced inhibition of nitric oxide production. Infect Immun. 2006;74:6272–6279.
   PubMed Web of Science ®Google Scholar
• Gomez MA, Contreras I, Halle M, et al. Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Sci Signal. 2009;2:ra58–ra.
   PubMed Web of Science ®Google Scholar
• Iniesta V, Carcelén J, Molano I, et al. Arginase I induction during Leishmania major infection mediates the development of disease. Infect Immun. 2005;73:6085–6090.
   PubMed Web of Science ®Google Scholar
• Badirzadeh A, Taheri T, Taslimi Y, et al. Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites. PLoS Negl Trop Dis. 2017;11:e0005774.
   PubMed Web of Science ®Google Scholar
• Boitz JM, Gilroy CA, Olenyik TD, et al. Arginase is essential for survival of Leishmania donovani promastigotes but not intracellular amastigotes. Infect Immun. 2017;85:e00554–16.
   PubMed Web of Science ®Google Scholar
• Muxel SM, Laranjeira-Silva MF, Zampieri RA, et al. Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism. Sci Rep. 2017;7:1–15.
   PubMed Web of Science ®Google Scholar
• Murray HW, Nathan CF. Macrophage microbicidal mechanisms in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani. J Exp Med. 1999;189:741–746.
   PubMed Web of Science ®Google Scholar
• Ball WB, Kar S, Mukherjee M, et al. Uncoupling protein 2 negatively regulates mitochondrial reactive oxygen species generation and induces phosphatase-mediated anti-inflammatory response in experimental visceral leishmaniasis. J Immunol. 2011;187:1322–1332.
   PubMed Web of Science ®Google Scholar
• Gupta AK, Ghosh K, Palit S, et al. Leishmania donovani inhibits inflammasome‐dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2. FASEB J. 2017;31:5087–5101.
   PubMed Web of Science ®Google Scholar
• Gantt KR, Goldman TL, McCormick ML, et al. Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. J Immunol. 2001;167:893–901.
   PubMed Web of Science ®Google Scholar
• Khouri R, Bafica A, Silva Mda P, et al. IFN-beta impairs superoxide-dependent parasite killing in human macrophages: evidence for a deleterious role of SOD1 in cutaneous leishmaniasis. J Immunol. 2009;182:2525–2531.
   PubMed Web of Science ®Google Scholar
• Abdalla MY, Ahmad IM, Switzer B, et al. Induction of heme oxygenase-1 contributes to survival of mycobacterium abscessus in human macrophages-like THP-1 cells. Redox Biol. 2015;4:328–339.
   PubMed Web of Science ®Google Scholar
• Mitterstiller AM, Haschka D, Dichtl S, et al. Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection. Cell Microbiol. 2016;18:1374–1389.
   PubMed Web of Science ®Google Scholar
• Luz NF, Andrade BB, Feijó DF, et al. Heme oxygenase-1 promotes the persistence of Leishmania chagasi infection. J Immunol. 2012;188:4460–4467.
   PubMed Web of Science ®Google Scholar
• Pham N-K, Mouriz J, Kima PE. Leishmania pifanoi amastigotes avoid macrophage production of superoxide by inducing heme degradation. Infect Immun. 2005;73:8322–8333.
   PubMed Web of Science ®Google Scholar
• Saha S, Basu M, Guin S, et al. Leishmania donovani exploits macrophage heme oxygenase-1 to neutralize oxidative burst and TLR signaling–dependent host defense. J Immunol. 2019;202:827–840.
   PubMed Web of Science ®Google Scholar
• Olivier M, Brownsey RW, Reiner NE. Defective stimulus-response coupling in human monocytes infected with Leishmania donovani is associated with altered activation and translocation of protein kinase C. Proc Nat Acad Sci. 1992;89:7481–7485.
   PubMed Web of Science ®Google Scholar
• Lodge R, Descoteaux A. Phagocytosis of Leishmania donovani amastigotes is Rac1 dependent and occurs in the absence of NADPH oxidase activation. Eur J Immunol. 2006;36:2735–2744.
   PubMed Web of Science ®Google Scholar
• Lodge R, Descoteaux A. Leishmania donovani promastigotes induce periphagosomal F‐actin accumulation through retention of the GTPase Cdc42. Cell Microbiol. 2005;7:1647–1658.
   PubMed Web of Science ®Google Scholar
• Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94:909–950.
   PubMed Web of Science ®Google Scholar
• Lenaz G. Mitochondria and reactive oxygen species. Which role in physiology and pathology? Adv Exp Med Biol. 2012;942:93–136.
   PubMed Web of Science ®Google Scholar
• Gupta AK, Roy S, Das PK. Antileishmanial effect of the natural immunomodulator genipin through suppression of host negative regulatory protein UCP2. J Antimicrob Chemother. 2021;76:135–145.
   PubMed Web of Science ®Google Scholar
• Bhardwaj S, Srivastava N, Sudan R, et al. Leishmania interferes with host cell signaling to devise a survival strategy. J Biomed Biotechnol. 2010;2010:109189.
   PubMedGoogle Scholar
• Brubaker SW, Bonham KS, Zanoni I, et al. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol. 2015;33:257–290.
   PubMed Web of Science ®Google Scholar
• Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32:305–315.
   PubMed Web of Science ®Google Scholar
• Carrera L, Gazzinelli RT, Badolato R, et al. Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice. J Exp Med. 1996;183:515–526.
   PubMed Web of Science ®Google Scholar
• Belkaid Y, Butcher B, Sacks DL. Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: selective impairment of IL-12 induction in Leishmania-infected cells. Eur J Immunol. 1998;28:1389–1400.
   PubMed Web of Science ®Google Scholar
• Faria MS, Reis FC, Lima AP. Toll-like receptors in leishmania infections: guardians or promoters? J Parasitol Res. 2012;2012:930257.
   PubMedGoogle Scholar
• Tuon FF, Amato VS, Bacha HA, et al. Toll-like receptors and leishmaniasis. Infect Immun. 2008;76:866–872.
   PubMed Web of Science ®Google Scholar
• Becker I, Salaiza N, Aguirre M, et al. Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Mol Biochem Parasitol. 2003;130:65–74.
   PubMed Web of Science ®Google Scholar
• de Veer MJ, Curtis JM, Baldwin TM, et al. MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll‐like receptor 2 signaling. Eur J Immunol. 2003;33:2822–2831.
   PubMed Web of Science ®Google Scholar
• Bhattacharya P, Bhattacharjee S, Gupta G, et al. Arabinosylated Lipoarabinomannan—mediated protection in visceral Leishmaniasis through up-regulation of toll-like receptor 2 signaling: an immunoprophylactic approach. J Infect Dis. 2010;202:145–155.
   PubMed Web of Science ®Google Scholar
• Kavoosi G, Ardestani S, Kariminia A. The involvement of TLR2 in cytokine and reactive oxygen species (ROS) production by PBMCs in response to Leishmania major phosphoglycans (PGs). Parasitology. 2009;136:1193–1199.
   PubMed Web of Science ®Google Scholar
• Rossi M, Fasel N. How to master the host immune system? Leishmania parasites have the solutions! Int Immunol. 2018;30:103–111.
   PubMed Web of Science ®Google Scholar
• Hawn TR, Ozinsky A, Underhill DM, et al. Leishmania major activates IL-1α expression in macrophages through a MyD88-dependent pathway. Microbes Infect. 2002;4:763–771.
   PubMed Web of Science ®Google Scholar
• Muraille E, De Trez C, Brait M, et al. Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response. J Immunol. 2003;170:4237–4241.
   PubMed Web of Science ®Google Scholar
• Debus A, Glasner J, Rollinghoff M, et al. High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with Leishmania major are interleukin-4 dependent. Infect Immun. 2003;71:7215–7218.
   PubMed Web of Science ®Google Scholar
• Srivastava A, Singh N, Mishra M, et al. Identification of TLR inducing Th1-responsive Leishmania donovani amastigote-specific antigens. Mol Cell Biochem. 2012;359:359–368.
   PubMed Web of Science ®Google Scholar
• Kropf P, Freudenberg N, Kalis C, et al. Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a role for Toll‐like receptor 4 in the control of parasite replication. J Leukoc Biol. 2004;76:48–57.
   PubMed Web of Science ®Google Scholar
• Müller I, Freudenberg M, Kropf P, et al. Leishmania major infection in C57BL/10 mice differing at the Lps locus: a new non-healing phenotype. Med Microbiol Immunol. 1997;186:75–81.
   PubMed Web of Science ®Google Scholar
• Cezário GAG, Oliveira L, Peresi E, et al. Analysis of the expression of toll-like receptors 2 and 4 and cytokine production during experimental Leishmania chagasi infection. Memórias Inst Oswaldo Cruz. 2011;106:573–583.
   PubMed Web of Science ®Google Scholar
• Gallego C, Golenbock D, Gomez MA, et al. Toll-like receptors participate in macrophage activation and intracellular control of Leishmania (Viannia) panamensis. Infect Immun. 2011;79:2871–2879.
   PubMed Web of Science ®Google Scholar
• Karmakar S, Bhaumik SK, Paul J, et al. TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis. PLoS Pathog. 2012;8:e1002646.
   PubMed Web of Science ®Google Scholar
• Polari LP, Carneiro PP, Macedo M, et al. Leishmania braziliensis infection enhances toll-like receptors 2 and 4 expression and triggers TNF-α and IL-10 production in human cutaneous leishmaniasis. Front Cell Infect Microbiol. 2019;9:120.
   PubMed Web of Science ®Google Scholar
• Wesche H, Henzel WJ, Shillinglaw W, et al. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity. 1997;7:837–847.
   PubMed Web of Science ®Google Scholar
• Suzuki N, Suzuki S, Duncan GS, et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature. 2002;416:750–754.
   PubMed Web of Science ®Google Scholar
• Gupta P, Giri J, Srivastav S, et al. Leishmania donovani targets tumor necrosis factor receptor‐associated factor (TRAF) 3 for impairing TLR4‐mediated host response. FASEB J. 2014;28:1756–1768.
   PubMed Web of Science ®Google Scholar
• Srivastav S, Kar S, Chande AG, et al. Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signaling, to subvert host immune response. J Immunol. 2012;189:924–934.
   PubMed Web of Science ®Google Scholar
• Flandin JF, Chano F, Descoteaux A. RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon–γ‐primed macrophages. Eur J Immunol. 2006;36:411–420.
   PubMed Web of Science ®Google Scholar
• Ives A, Ronet C, Prevel F, et al. Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science. 2011;331:775–778.
   PubMed Web of Science ®Google Scholar
• Li Y, Ishii K, Hisaeda H, et al. IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice: is the effect mediated by the CpG signaling TLR9? Gene Ther. 2004;11:941–948.
   PubMed Web of Science ®Google Scholar
• Schleicher U, Liese J, Knippertz I, et al. NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs. J Exp Med. 2007;204:893–906.
   PubMed Web of Science ®Google Scholar
• Liese J, Schleicher U, Bogdan C. TLR9 signaling is essential for the innate NK cell response in murine cutaneous leishmaniasis. Eur J Immunol. 2007;37:3424–3434.
   PubMed Web of Science ®Google Scholar
• Lima-Junior DS, Costa DL, Carregaro V, et al. Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania. Nat Med. 2013;19:909–915.
   PubMed Web of Science ®Google Scholar
• Gurung P, Karki R, Vogel P, et al. An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasis. J Clin Invest. 2015;125:1329–1338.
   PubMed Web of Science ®Google Scholar
• Lefèvre L, Lugo-Villarino G, Meunier E, et al. The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum. Immunity. 2013;38:1038–1049.
   PubMed Web of Science ®Google Scholar
• Iborra S, Martínez-López M, Cueto FJ, et al. Leishmania uses mincle to target an inhibitory ITAM signaling pathway in dendritic cells that dampens adaptive immunity to infection. Immunity. 2016;45:788–801.
   PubMed Web of Science ®Google Scholar
• Takai Y, Kishimoto A, Inoue M, et al. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem. 1977;252:7603–7609.
   PubMed Web of Science ®Google Scholar
• Severn A, Wakelam MJ, Liew FY. The role of protein kinase C in the induction of nitric oxide synthesis by murine macrophages. Biochem Biophys Res Commun. 1992;188:997–1002.
   PubMed Web of Science ®Google Scholar
• Warzocha K, Bienvenu J, Coiffier B, et al. Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. Eur Cytokine Netw. 1995;6:83–96.
   PubMed Web of Science ®Google Scholar
• Turco SJ, Descoteaux A. The lipophosphoglycan of Leishmania parasites. Annu Rev Microbiol. 1992;46:65–94.
   PubMed Web of Science ®Google Scholar
• Descoteaux A, Turco SJ. Glycoconjugates in Leishmania infectivity. Biochim Biophys Acta. 1999;1455:341–352.
   PubMed Web of Science ®Google Scholar
• McNeely TB, Rosen G, Londner MV, et al. Inhibitory effects on protein kinase C activity by lipophosphoglycan fragments and glycosylphosphatidylinositol antigens of the protozoan parasite Leishmania. Biochem J. 1989;259:601–604.
   PubMed Web of Science ®Google Scholar
• Ghosh S, Bhattacharyya S, Das S, et al. Generation of ceramide in murine macrophages infected with Leishmania donovani alters macrophage signaling events and aids intracellular parasitic survival. Mol Cell Biochem. 2001;223:47–60.
   PubMed Web of Science ®Google Scholar
• Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci. 2004;117:1281–1283.
   PubMed Web of Science ®Google Scholar
• Forget G, Gregory DJ, Olivier M. Proteasome-mediated degradation of STAT1α following infection of macrophages with Leishmania donovani. J Biol Chem. 2005;280:30542–30549.
   PubMed Web of Science ®Google Scholar
• Ray M, Gam AA, Boykins RA, et al. Inhibition of interferon-gamma signaling by Leishmania donovani. J Infect Dis. 2000;181:1121–1128.
   PubMed Web of Science ®Google Scholar
• Bertholet S, Dickensheets HL, Sheikh F, et al. Leishmania donovani-induced expression of suppressor of cytokine signaling 3 in human macrophages: a novel mechanism for intracellular parasite suppression of activation. Infect Immun. 2003;71:2095–2101.
   PubMed Web of Science ®Google Scholar
• Matte C, Descoteaux A. Leishmania donovani amastigotes impair gamma interferon-induced STAT1alpha nuclear translocation by blocking the interaction between STAT1alpha and importin-alpha5. Infect Immun. 2010;78:3736–3743.
   PubMed Web of Science ®Google Scholar
• Seger R, Krebs EG. The MAPK signaling cascade. FASEB J. 1995;9:726–735.
   PubMed Web of Science ®Google Scholar
• Cobb MH. MAP kinase pathways. Prog Biophys Mol Biol. 1999;71:479–500.
   PubMed Web of Science ®Google Scholar
• MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol. 1997;15:323–350.
   PubMed Web of Science ®Google Scholar
• Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl). 1996;74:589–607.
   PubMed Web of Science ®Google Scholar
• Murphy TL, Cleveland MG, Kulesza P, et al. Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol. 1995;15:5258–5267.
   PubMed Web of Science ®Google Scholar
• Kamijo R, Harada H, Matsuyama T, et al. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science. 1994;263:1612–1615.
   PubMed Web of Science ®Google Scholar
• Nandan D, Lo R, Reiner NE. Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani. Infect Immun. 1999;67:4055–4063.
   PubMed Web of Science ®Google Scholar
• Martiny A, Meyer-Fernandes JR, de Souza W, et al. Altered tyrosine phosphorylation of ERK1 MAP kinase and other macrophage molecules caused by Leishmania amastigotes. Mol Biochem Parasitol. 1999;102:1–12.
   PubMed Web of Science ®Google Scholar
• Kar S, Ukil A, Sharma G, et al. MAPK-directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral leishmaniasis: involvement of distinct protein kinase C isoforms. J Leukoc Biol. 2010;88:9–20.
   PubMed Web of Science ®Google Scholar
• Hannun YA. Functions of ceramide in coordinating cellular responses to stress. Science. 1996;274:1855–1859.
   PubMed Web of Science ®Google Scholar
• Cameron P, McGachy A, Anderson M, et al. Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-κB signaling pathway. J Immunol. 2004;173:3297–3304.
   PubMed Web of Science ®Google Scholar
• Awasthi A, Mathur R, Khan A, et al. CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response. J Exp Med. 2003;197:1037–1043.
   PubMed Web of Science ®Google Scholar
• Junghae M, Raynes JG. Activation of p38 mitogen-activated protein kinase attenuates Leishmania donovani infection in macrophages. Infect Immun. 2002;70:5026–5035.
   PubMed Web of Science ®Google Scholar
• Feng CG, Scanga CA, Collazo-Custodio CM, et al. Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)-and TLR4-deficient animals. J Immunol. 2003;171:4758–4764.
   PubMed Web of Science ®Google Scholar
• Balaraman S, Singh VK, Tewary P, et al. Leishmania lipophosphoglycan activates the transcription factor activating protein 1 in J774A. 1 macrophages through the extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase. Mol Biochem Parasitol. 2005;139:117–127.
   PubMed Web of Science ®Google Scholar
• Hallé M, Gomez MA, Stuible M, et al. The Leishmania surface protease GP63 cleaves multiple intracellular proteins and actively participates in p38 mitogen-activated protein kinase inactivation. J Biol Chem. 2009;284:6893–6908.
   PubMed Web of Science ®Google Scholar
• Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495–516.
   PubMed Web of Science ®Google Scholar
• Sly LM, Hingley-Wilson SM, Reiner NE, et al. Survival of mycobacterium tuberculosis in host macrophages involves resistance to apoptosis dependent upon induction of antiapoptotic Bcl-2 family member Mcl-1. J Immunol. 2003;170:430–437.
   PubMed Web of Science ®Google Scholar
• Wang FY, Wang XM, Wang C, et al. Suppression of Mcl-1 induces apoptosis in mouse peritoneal macrophages infected with mycobacterium tuberculosis. Microbiol Immunol. 2016;60:215–227.
   PubMed Web of Science ®Google Scholar
• Das S, Ghosh AK, Singh S, et al. Unmethylated CpG motifs in the L. donovani DNA regulate TLR9-dependent delay of programmed cell death in macrophages. J Leukoc Biol. 2015;97:363–378.
   PubMed Web of Science ®Google Scholar
• Giri J, Srivastav S, Basu M, et al. Leishmania donovani exploits Myeloid Cell Leukemia 1 (MCL-1) protein to prevent mitochondria-dependent host cell apoptosis. J Biol Chem. 2016;291:3496–3507.
   PubMed Web of Science ®Google Scholar
• Pandey RK, Mehrotra S, Sharma S, et al. Leishmania donovani-induced increase in macrophage Bcl-2 favors parasite survival. Front Immunol. 2016;7:456.
   PubMed Web of Science ®Google Scholar
• Srivastav S, Basu Ball W, Gupta P, et al. Leishmania donovani prevents oxidative burst-mediated apoptosis of host macrophages through selective induction of suppressors of cytokine signaling (SOCS) proteins. J Biol Chem. 2014;289:1092–1105.
   PubMed Web of Science ®Google Scholar
• Gupta P, Srivastav S, Saha S, et al. Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of beta-catenin and FOXO-1. Cell Death Differ. 2016;23:1815–1826.
   PubMed Web of Science ®Google Scholar
• Chuenkova MV, Furnari FB, Cavenee WK, et al. Trypanosoma cruzi trans-sialidase: a potent and specific survival factor for human Schwann cells by means of phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci U S A. 2001;98:9936–9941.
   PubMed Web of Science ®Google Scholar
• Han J, Pedersen JS, Kwon SC, et al. Posttranscriptional crossregulation between Drosha and DGCR8. Cell. 2009;136:75–84.
   PubMed Web of Science ®Google Scholar
• Finnegan EF, Pasquinelli AE. MicroRNA biogenesis: regulating the regulators. Crit Rev Biochem Mol Biol. 2013;48:51–68.
   PubMed Web of Science ®Google Scholar
• Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9:102–114.
   PubMed Web of Science ®Google Scholar
• Gulyaeva LF, Kushlinskiy NE. Regulatory mechanisms of microRNA expression. J Transl Med. 2016;14:143.
   PubMed Web of Science ®Google Scholar
• Thulin P, Wei T, Werngren O, et al. MicroRNA-9 regulates the expression of peroxisome proliferator-activated receptor delta in human monocytes during the inflammatory response. Int J Mol Med. 2013;31:1003–1010.
   PubMed Web of Science ®Google Scholar
• Taganov KD, Boldin MP, Chang KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12481–12486.
   PubMed Web of Science ®Google Scholar
• Bi J, Zeng X, Zhao L, et al. miR-181a induces macrophage polarized to M2 phenotype and promotes M2 macrophage-mediated tumor cell metastasis by targeting KLF6 and C/EBPalpha. Mol Ther Nucleic Acids. 2016;5:e368.
   PubMedGoogle Scholar
• Yu A, Zhang T, Duan H, et al. MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-alpha pathway in intracerebral hemorrhage. Immunol Lett. 2017;182:1–11.
   PubMed Web of Science ®Google Scholar
• Banerjee S, Xie N, Cui H, et al. MicroRNA let-7c regulates macrophage polarization. J Immunol. 2013;190:6542–6549.
   PubMed Web of Science ®Google Scholar
• Qi J, Qiao Y, Wang P, et al. microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-kappaB1 in murine macrophages. FEBS Lett. 2012;586:1201–1207.
   PubMed Web of Science ®Google Scholar
• Lin L, Lin H, Wang L, et al. miR-130a regulates macrophage polarization and is associated with non-small cell lung cancer. Oncol Rep. 2015;34:3088–3096.
   PubMed Web of Science ®Google Scholar
• Sahu SK, Kumar M, Chakraborty S, et al. MicroRNA 26a (miR-26a)/KLF4 and CREB-C/EBPbeta regulate innate immune signaling, the polarization of macrophages and the trafficking of Mycobacterium tuberculosis to lysosomes during infection. PLoS Pathog. 2017;13:e1006410.
   PubMed Web of Science ®Google Scholar
• Zhong Y, Yi C. MicroRNA-720 suppresses M2 macrophage polarization by targeting GATA3. Biosci Rep. 2016;36(4): e00363.
   PubMedGoogle Scholar
• Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–737.
   PubMed Web of Science ®Google Scholar
• Gregory DJ, Olivier M. Subversion of host cell signalling by the protozoan parasite Leishmania. Parasitology. 2005;130(Suppl):S27–35.
   PubMedGoogle Scholar
• Saradna A, Do DC, Kumar S, et al. Macrophage polarization and allergic asthma. Transl Res. 2018;191:1–14.
   PubMed Web of Science ®Google Scholar
• Tomiotto-Pellissier F, Bortoleti B, Assolini JP, et al. Macrophage polarization in Leishmaniasis: broadening horizons. Front Immunol. 2018;9:2529.
   PubMed Web of Science ®Google Scholar
• Silva RL, Santos MB, Almeida PL, et al. sCD163 levels as a biomarker of disease severity in leprosy and visceral leishmaniasis. PLoS Negl Trop Dis. 2017;11:e0005486.
   PubMed Web of Science ®Google Scholar
• Kumar A, Das S, Mandal A, et al. Leishmania infection activates host mTOR for its survival by M2 macrophage polarization. Parasite Immunol. 2018;40:e12586.
   PubMed Web of Science ®Google Scholar
• Lima JB, Araujo-Santos T, Lazaro-Souza M, et al. Leishmania infantum lipophosphoglycan induced-Prostaglandin E2 production in association with PPAR-gamma expression via activation of toll like receptors-1 and 2. Sci Rep. 2017;7:14321.
   PubMed Web of Science ®Google Scholar
• Geraci NS, Tan JC, McDowell MA. Characterization of microRNA expression profiles in Leishmania-infected human phagocytes. Parasite Immunol. 2015;37:43–51.
   PubMed Web of Science ®Google Scholar
• Tiwari N, Kumar V, Gedda MR, et al. Identification and characterization of miRNAs in response to Leishmania donovani infection: delineation of their roles in macrophage dysfunction. Front Microbiol. 2017;8:314.
   PubMed Web of Science ®Google Scholar
• Lemaire J, Mkannez G, Guerfali FZ, et al. MicroRNA expression profile in human macrophages in response to Leishmania major infection. PLoS Negl Trop Dis. 2013;7:e2478.
   PubMed Web of Science ®Google Scholar
• Li H, Jiang T, Li MQ, et al. Transcriptional regulation of macrophages polarization by microRNAs. Front Immunol. 2018;9:1175.
   PubMed Web of Science ®Google Scholar
• Aoki JI, Muxel SM, Zampieri RA, et al. Differential immune response modulation in early Leishmania amazonensis infection of BALB/c and C57BL/6 macrophages based on transcriptome profiles. Sci Rep. 2019;9:19841.
   PubMed Web of Science ®Google Scholar
• Nimsarkar P, Ingale P, Singh S. Systems studies uncover miR-146a as a target in leishmania major infection model. ACS Omega. 2020;5:12516–12526.
   PubMed Web of Science ®Google Scholar
• Das S, Mukherjee S, Ali N. Super enhancer-mediated transcription of miR146a-5p drives M2 polarization during Leishmania donovani infection. PLoS Pathog. 2021;17:e1009343.
   PubMed Web of Science ®Google Scholar
• Ghosh J, Bose M, Roy S, et al. Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection. Cell Host Microbe. 2013;13:277–288.
   PubMed Web of Science ®Google Scholar
• Loria AD, Dattilo V, Santoro D, et al. Expression of serum exosomal miRNA 122 and lipoprotein levels in dogs naturally infected by leishmania infantum: a preliminary study. Animals (Basel). 2020;10(1): 100.
   PubMedGoogle Scholar
• Colineau L, Lambertz U, Fornes O, et al. c-Myc is a novel Leishmania virulence factor by proxy that targets the host miRNA system and is essential for survival in human macrophages. J Biol Chem. 2018;293:12805–12819.
   PubMed Web of Science ®Google Scholar
• Muxel SM, Laranjeira-Silva MF, Zampieri RA, et al. Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism. Sci Rep. 2017;7:44141.
   PubMed Web of Science ®Google Scholar
• Muxel SM, Aoki JI, Fernandes JCR, et al. Arginine and polyamines fate in leishmania infection. Front Microbiol. 2017;8:2682.
   PubMed Web of Science ®Google Scholar
• Fernandes JCR, Aoki JI, Maia Acuna S, et al. Melatonin and Leishmania amazonensis infection altered miR-294, miR-30e, and miR-302d Impacting on Tnf, Mcp-1, and Nos2 expression. Front Cell Infect Microbiol. 2019;9:60.
   PubMed Web of Science ®Google Scholar
• Oghumu S, Lezama-Davila CM, Isaac-Marquez AP, et al. Role of chemokines in regulation of immunity against leishmaniasis. Exp Parasitol. 2010;126:389–396.
   PubMed Web of Science ®Google Scholar
• Guerfali FZ, Laouini D, Guizani-Tabbane L, et al. Simultaneous gene expression profiling in human macrophages infected with Leishmania major parasites using SAGE. BMC Genomics. 2008;9:238.
   PubMed Web of Science ®Google Scholar
• Degrossoli A, Bosetto MC, Lima CB, et al. Expression of hypoxia-inducible factor 1 alpha in mononuclear phagocytes infected with Leishmania amazonensis. Immunol Lett. 2007;114:119–125.
   PubMed Web of Science ®Google Scholar
• Kumar V, Kumar A, Das S, et al. Leishmania donovani activates hypoxia inducible factor-1 alpha and miR-210 for survival in macrophages by downregulation of NF-kappaB mediated pro-inflammatory immune response. Front Microbiol. 2018;9:385.
   PubMed Web of Science ®Google Scholar
• Lago TS, Silva JA, Lago EL, et al. The miRNA 361-3p, a regulator of GZMB and TNF is associated with therapeutic failure and longer time healing of cutaneous leishmaniasis caused by L. (viannia) braziliensis. Front Immunol. 2018;9:2621.
   PubMed Web of Science ®Google Scholar
• Souza MA, Ramos-Sanchez EM, Muxel SM, et al. miR-548d-3p alters parasite growth and inflammation in Leishmania (Viannia) braziliensis infection. Front Cell Infect Microbiol. 2021;11:687647.
   PubMed Web of Science ®Google Scholar
• Bragato JP, Melo LM, Venturin GL, et al. Relationship of peripheral blood mononuclear cells miRNA expression and parasitic load in canine visceral leishmaniasis. PLoS One. 2018;13:e0206876.
   PubMed Web of Science ®Google Scholar
• Diotallevi A, De Santi M, Buffi G, et al. Leishmania infection induces microRNA hsa-miR-346 in human cell line-derived macrophages. Front Microbiol. 2018;9:1019.
   PubMed Web of Science ®Google Scholar
• Mukherjee B, Paul J, Mukherjee S, et al. Antimony-resistant Leishmania donovani exploits miR-466i to deactivate host MyD88 for regulating IL-10/IL-12 levels during early hours of infection. J Immunol. 2015;195:2731–2742.
   PubMed Web of Science ®Google Scholar
• Muxel SM, Acuna SM, Aoki JI, et al. Toll-like receptor and miRNA-let-7e expression alter the inflammatory response in leishmania amazonensis-infected macrophages. Front Immunol. 2018;9:2792.
   PubMed Web of Science ®Google Scholar
• Franco LH, Fleuri AKA, Pellison NC, et al. Autophagy downstream of endosomal toll-like receptor signaling in macrophages is a key mechanism for resistance to Leishmania major infection. J Biol Chem. 2017;292:13087–13096.
   PubMed Web of Science ®Google Scholar
• Singh AK, Pandey RK, Shaha C, et al. MicroRNA expression profiling of Leishmania donovani-infected host cells uncovers the regulatory role of MIR30A-3p in host autophagy. Autophagy. 2016;12:1817–1831.
   PubMed Web of Science ®Google Scholar
• Kumar V, Das S, Kumar A, et al. Leishmania donovani infection induce differential miRNA expression in CD4+ T cells. Sci Rep. 2020;10:3523.
   PubMed Web of Science ®Google Scholar
• Rana T, Misra S, Mittal MK, et al. Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. J Biol Chem. 2011;286:6614–6626.
   PubMed Web of Science ®Google Scholar
• Fernandes MC, Dillon LA, Belew AT, et al. Dual transcriptome profiling of leishmania-infected human macrophages reveals distinct reprogramming signatures. mBio. 2016;7(3): e00027–16.
   Web of Science ®Google Scholar
• Parmar N, Chandrakar P, Kar S. Leishmania donovani subverts host immune response by epigenetic reprogramming of macrophage M(Lipopolysaccharides + IFN-gamma)/M(IL-10) polarization. J Immunol. 2020;204:2762–2778.
   PubMed Web of Science ®Google Scholar
• Calegari-Silva TC, Vivarini AC, Pereira RMS, et al. Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism. Eur J Immunol. 2018;48:1188–1198.
   PubMed Web of Science ®Google Scholar
• Roy G, Brar HK, Muthuswami R, et al. Epigenetic regulation of defense genes by histone deacetylase1 in human cell line-derived macrophages promotes intracellular survival of Leishmania donovani. PLoS Negl Trop Dis. 2020;14:e0008167.
   PubMed Web of Science ®Google Scholar
• Kamhawi S, Serafim TD. Leishmania: a maestro in epigenetic manipulation of macrophage inflammasomes. Trends Parasitol. 2020;36:498–501.
   PubMed Web of Science ®Google Scholar
• Lecoeur H, Prina E, Rosazza T, et al. Targeting macrophage histone H3 modification as a leishmania strategy to dampen the NF-kappaB/NLRP3-mediated inflammatory response. Cell Rep. 2020;30:1870–82 e4.
   PubMed Web of Science ®Google Scholar
• Kumar A, Pandey SC, Samant M. A spotlight on the diagnostic methods of a fatal disease Visceral Leishmaniasis. Parasite Immunol. 2020;42:e12727.
   PubMed Web of Science ®Google Scholar
• Saha S, Goswami R, Pramanik N, et al. Easy test for visceral Leishmaniasis and post-Kala-azar Dermal Leishmaniasis. Emerg Infect Dis. 2011;17:1304–1306.
   PubMed Web of Science ®Google Scholar
• Ejazi SA, Bhattacharya P, Bakhteyar MA, et al. Noninvasive diagnosis of Visceral Leishmaniasis: development and evaluation of two urine-based immunoassays for detection of leishmania donovani infection in India. PLoS Negl Trop Dis. 2016;10:e0005035.
   PubMed Web of Science ®Google Scholar
• Reimao JQ, Coser EM, Lee MR, et al. Laboratory diagnosis of cutaneous and Visceral Leishmaniasis: current and future methods. Microorganisms. 2020;8(11): 1632.
   PubMed Web of Science ®Google Scholar
• Ejazi SA, Ghosh S, Bhattacharyya A, et al. Investigation of the antigenicity and protective efficacy of Leishmania promastigote membrane antigens in search of potential diagnostic and vaccine candidates against visceral leishmaniasis. Parasit Vectors. 2020;13:272.
   PubMed Web of Science ®Google Scholar
• Didwania N, Ejazi SA, Chhajer R, et al. Evaluation of cysteine protease C of Leishmania donovani in comparison with glycoprotein 63 and elongation factor 1 alpha for diagnosis of human visceral leishmaniasis and for posttreatment follow-up response. J Clin Microbiol. 2020;58(11): e00213–20.
   PubMed Web of Science ®Google Scholar
• Ejazi SA, Ghosh S, Saha S, et al. Author correction: a multicentric evaluation of dipstick test for serodiagnosis of visceral leishmaniasis in India, Nepal, Sri Lanka, Brazil, Ethiopia and Spain. Sci Rep. 2021;11:3967.
   PubMed Web of Science ®Google Scholar
• Ejazi SA, Choudhury ST, Bhattacharyya A, et al. Development and clinical evaluation of serum and urine-based lateral flow tests for diagnosis of human Visceral Leishmaniasis. Microorganisms. 2021;9(7): 1369.
   PubMed Web of Science ®Google Scholar
• Burza S, Croft SL, Boelaert M. Leishmaniasis. Lancet. 2018;392:951–970.
   PubMed Web of Science ®Google Scholar
• Ejazi SA, Ali N. Developments in diagnosis and treatment of visceral leishmaniasis during the last decade and future prospects. Expert Rev Anti Infect Ther. 2013;11:79–98.
   PubMed Web of Science ®Google Scholar
• Chowdhury AR, Mandal S, Goswami A, et al. Dihydrobetulinic acid induces apoptosis in Leishmania donovani by targeting DNA topoisomerase I and II: implications in antileishmanial therapy. Mol Med. 2003;9:26–36.
   PubMed Web of Science ®Google Scholar
• Chhajer R, Bhattacharyya A, Didwania N, et al. Leishmania donovani Aurora kinase: a promising therapeutic target against visceral leishmaniasis. Biochim Biophys Acta. 2016;1860:1973–1988.
   PubMed Web of Science ®Google Scholar
• van Griensven J, Balasegaram M, Meheus F, et al. Combination therapy for visceral leishmaniasis. Lancet Infect Dis. 2010;10:184–194.
   PubMed Web of Science ®Google Scholar
• Veeken H, Ritmeijer K, Seaman J, et al. A randomized comparison of branded sodium stibogluconate and generic sodium stibogluconate for the treatment of visceral leishmaniasis under field conditions in Sudan. Trop Med Int Health. 2000;5:312–317.
   PubMed Web of Science ®Google Scholar
• Roychoudhury J, Sinha R, Ali N. Therapy with sodium stibogluconate in stearylamine-bearing liposomes confers cure against SSG-resistant Leishmania donovani in BALB/c mice. PLoS One. 2011;6:e17376.
   PubMed Web of Science ®Google Scholar
• Musa A, Khalil E, Hailu A, et al. Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial. PLoS Negl Trop Dis. 2012;6:e1674.
   PubMed Web of Science ®Google Scholar
• Paila YD, Saha B, Chattopadhyay A. Amphotericin B inhibits entry of Leishmania donovani into primary macrophages. Biochem Biophys Res Commun. 2010;399:429–433.
   PubMed Web of Science ®Google Scholar
• Chattopadhyay A, Jafurulla M. A novel mechanism for an old drug: amphotericin B in the treatment of visceral leishmaniasis. Biochem Biophys Res Commun. 2011;416:7–12.
   PubMed Web of Science ®Google Scholar
• Singh S, Sivakumar R. Challenges and new discoveries in the treatment of leishmaniasis. J Infect Chemother. 2004;10:307–315.
   PubMedGoogle Scholar
• Thakur C, Kumar A, Mitra G, et al. Impact of amphotericin-B in the treatment of kala-azar on the incidence of PKDL in Bihar, India. Indian J Med Res. 2008;128:38.
   PubMed Web of Science ®Google Scholar
• Olliaro PL, Guerin PJ, Gerstl S, et al. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980–2004. Lancet Infect Dis. 2005;5:763–774.
   PubMed Web of Science ®Google Scholar
• Goswami RP, Goswami RP, Das S, et al. Short-course treatment regimen of Indian Visceral Leishmaniasis with an Indian liposomal amphotericin B preparation (Fungisome). Am J Trop Med Hyg. 2016;94:93–98.
   PubMed Web of Science ®Google Scholar
• Sundar S, Sinha PK, Rai M, et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet. 2011;377:477–486.
   PubMed Web of Science ®Google Scholar
• Mishra J, Dey A, Singh N, et al. Evaluation of toxicity & therapeutic efficacy of a new liposomal formulation of amphotericin B in a mouse model. Indian J Med Res. 2013;137:767.
   PubMed Web of Science ®Google Scholar
• Asad M, Bhattacharya P, Banerjee A, et al. Therapeutic and immunomodulatory activities of short-course treatment of murine visceral leishmaniasis with KALSOME™ 10, a new liposomal amphotericin B. BMC Infect Dis. 2015;15:1–12.
   PubMed Web of Science ®Google Scholar
• Shadab M, Jha B, Asad M, et al. Apoptosis-like cell death in Leishmania donovani treated with KalsomeTM10, a new liposomal amphotericin B. PLoS One. 2017;12:e0171306.
   PubMed Web of Science ®Google Scholar
• Sundar S, Chakravarty J. Liposomal amphotericin B and leishmaniasis: dose and response. J Glob Infect Dis. 2010;2:159–166.
   PubMedGoogle Scholar
• Sundar S, Jha T, Thakur C, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med. 2002;347:1739–1746.
   PubMed Web of Science ®Google Scholar
• Croft SL, Neal RA, Pendergast W, et al. The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochem Pharmacol. 1987;36:2633–2636.
   PubMed Web of Science ®Google Scholar
• Paris C, Loiseau PM, Bories C, et al. Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother. 2004;48:852–859.
   PubMed Web of Science ®Google Scholar
• Ponte CB, Alves ÉAR, Sampaio RNR, et al. Miltefosine enhances phagocytosis but decreases nitric oxide production by peritoneal macrophages of C57BL/6 mice. Int Immunopharmacol. 2012;13:114–119.
   PubMed Web of Science ®Google Scholar
• Gupta R, Kushawaha PK, Samant M, et al. Treatment of Leishmania donovani-infected hamsters with miltefosine: analysis of cytokine mRNA expression by real-time PCR, lymphoproliferation, nitrite production and antibody responses. J Antimicrob Chemother. 2012;67:440–443.
   PubMed Web of Science ®Google Scholar
• Mukhopadhyay D, Das NK, Roy S, et al. Miltefosine effectively modulates the cytokine milieu in Indian post kala-azar dermal leishmaniasis. J Infect Dis. 2011;204:1427–1436.
   PubMed Web of Science ®Google Scholar
• Avorn J. Learning about the safety of drugs—a half-century of evolution. N Engl J Med. 2011;365:2151–2153.
   PubMed Web of Science ®Google Scholar
• Asherson RA, Gunter K, Daya D, et al. Multiple autoimmune diseases in a young woman: tuberculosis and splenectomy as possible triggering factors? Another example of the “mosaic” of autoimmunity. J Rheumatol. 2008;35:1224–1227.
   PubMed Web of Science ®Google Scholar
• Kar S, Sharma G, Das PK. Fucoidan cures infection with both antimony-susceptible and-resistant strains of Leishmania donovani through Th1 response and macrophage-derived oxidants. J Antimicrob Chemother. 2011;66:618–625.
   PubMed Web of Science ®Google Scholar
• Sharma G, Kar S, Ball WB, et al. The curative effect of fucoidan on visceral leishmaniasis is mediated by activation of MAP kinases through specific protein kinase C isoforms. Cell Mol Immunol. 2014;11:263–274.
   PubMed Web of Science ®Google Scholar
• Descoteaux A. Leishmania cysteine proteinases: virulence factors in quest of a function. Parasitol Today (Personal ed). 1998;14:220–221.
   Google Scholar
• Das L, Datta N, Bandyopadhyay S, et al. Successful therapy of lethal murine visceral leishmaniasis with cystatin involves up-regulation of nitric oxide and a favorable T cell response. J Immunol. 2001;166:4020–4028.
   PubMed Web of Science ®Google Scholar
• Kar S, Ukil A, Das PK. Cystatin cures visceral leishmaniasis by NF‐κB‐mediated proinflammatory response through co‐ordination of TLR/MyD88 signaling with p105‐Tpl2‐ERK pathway. Eur J Immunol. 2011;41:116–127.
   PubMed Web of Science ®Google Scholar
• Ukil A, Biswas A, Das T, et al. 18β-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-κB. J Immunol. 2005;175:1161–1169.
   PubMed Web of Science ®Google Scholar
• Ukil A, Kar S, Srivastav S, et al. Curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular MAP kinases. PLoS One. 2011;6:e29062.
   PubMed Web of Science ®Google Scholar
• Bhattacharjee S, Bhattacharjee A, Majumder S, et al. Glycyrrhizic acid suppresses Cox-2-mediated anti-inflammatory responses during Leishmania donovani infection. J Antimicrob Chemother. 2012;67:1905–1914.
   PubMed Web of Science ®Google Scholar
• Bhattacharjee A, Majumder S, Majumdar SB, et al. Co-administration of glycyrrhizic acid with the antileishmanial drug sodium antimony gluconate (SAG) cures SAG-resistant visceral leishmaniasis. Int J Antimicrob Agents. 2015;45:268–277.
   PubMed Web of Science ®Google Scholar
• Dinesh N, Neelagiri S, Kumar V, et al. Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels. Exp Parasitol. 2017;176:21–29.
   PubMed Web of Science ®Google Scholar
• Sheikhi S, Khamesipour A, Radjabian T, et al. Immunotherapeutic effects of glycyrrhiza glabra and glycyrrhizic acid on leishmania major infected BALB/C mice. Parasite Immunol. 2021(44):e12879.
   PubMed Web of Science ®Google Scholar